N-(hydroxy-or methoxy-alkyl)-2-(n&#39;-(hydroxy or methoxy-alkyl)-phenyl-amino)-imidazolines-(2) and salts thereof

ABSTRACT

COMPOUNDS OF THE FORMULA   1-R5,2-((R1,R2,R3-PHENYL)-N(-R4)-)-2-IMIDAZOLIDINE AND NON-TOXIC, PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF; THE COMPOUNDS AS WELL AS THE SALTS ARE USEFUL AS HYPOTENSIVES.   R IS HYDROGEN OR METHYL, N IS AN INTEGER FROM 1 TO 6, INCLUSIVE, AND X IS AN INTEGER FROM 1 TO 3, INCLUSIVE,   WHERE   -CNH2N+1-X(OR)X   R1, R2 AND R3, WHICH MAY BE IDENTICAL TO OR DIFFERENT FROM EACH OTHER, ARE EACH HYDROGEN, CHLORINE, FLUORINE, BROMINE, CYANO, TRIFLUOROMETHYL, ALKYL OF 1 TO 3 CARBON ATOMS OR ALKOXY OF 1 TO 3 CARBON ATOMS, AND R4 AND R5, WHICH MUST BE DIFFERENT FROM EACH OTHER, ARE EACH HYDROGEN OR   WHEREIN

" United States Patent Oflice 3,773,767 Patented Nov. 20, 1973 Claimspriority, application Germany, Apr. 6, 1970,

Int. Cl. C076 49/34 US. Cl. 260254 v 8 Claims ABSTRACT OF THE DISCLOSURECompounds of the formula wherein R R and R which may be identical to ordifferent from each other, are each hydrogen, chlorine, fluorine,bromine, cyano, trifluoromethyl, alkyl of 1 to 3 carbon atoms or alkoxyof 1 to 3 carbon atoms, and

R and R which must be diflerent from each other, are

eachhydrogen or cnumniwmx where a R is hydrogen or methyl, n is aninteger from 1 to 6, inclusive, and x is an integer from 1 to 3,inclusive,

and non-toxic, pharmacologically acceptable acid addition salts thereof;the compounds. as well as the salts are useful as hypotensives.

This invention relates to novel derivatives ofN-hydroxyalkyl-2-phenylamino-imidazolines-(2) and non-toxic acidadditio'ns salts thereof,as well as to various methods of preparingthese compounds.

More particularly, 'the present invention relates to a novel class ofcompounds represented by the formula 1 j l f,

i R: 'R

r n. a

R .Rfima R which 'rnay beidentical mp; (lifierent from each other, areeach hydrogen,"1 chlorine, fluorine, bromine, cyano, trifluoromethyl,alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms, and

each hydrogen or 1, 1 v V n 2n -i x x J where w p R is hydrogen'ormethyl, nis an integer, from 1 too, inclusive, and ,x is an integer;from 1 to 3, inclusiye, --1- and, non-toxic,"pharmacologic-allyacceptable acid 'a'd'di-" larly convenient and efficient.

tion salts thereof.

Within the genus defined by Formula I, a particularly preferredsub-generic class of compounds is that represented by the formulawherein R and R have the same meanings as in Formula I and R is chlorineor methyl.

Other sub-genuses are those represented by the formulas R: It :1

Ra Iii \N- N R4 in and N H 1 i,

wherein R is chlorine, bromine, trifiuoro-methyl or cyano,

R is hydrogen, methyl, chlorine or bromine,

R is monohydroxy-alkyl of 1 to 4 carbon atoms, 2,3-dihydroxy-propyl ormethoxy-methyl, and

R is monohydroxy-alkyl'of 1 to 6 carbon atoms,

2 math-methyl: X 2365 ishl zrh vll R and ,R which must be differentfromeach Qther,-,;are 1 hydroxymethyl 2 dlcblgtoTphePYl'kafllmol" andnon-toxic, pharmacologically acceptable zicidaddiparticu g.

METHOD A By reacting a 2-phenylamino-imidazoline-(Z) of the formula N QM1 RI H H (II) wherein R R and R have the same meanings as in Formula I,with an oxyalkyl halide of the formula HalC H OH) (III) wherein R, n andx have the meanings defined in connection with Formula I and Hal ischlorine, bromine or iodine; or with an aldehyde of the formula H (IV)wherein R, n and x have the same meanings as in Formula I; or with anepoxide of the formula HzCwC H-Cn-:H2n-1(0 R) 1-] wherein R, n and xhave the same meanings as in Formula I.

METHOD B By reacting a substituted aniline of the formula wherein R Rand K; have the same meanings as in Formula I, R; has the meaningsdefined in Formula I except hydrogen, and A is SCH: S

-C G or CEN NH NH:

with ethylenediamine or an acid addition salt thereof.

7 METHOD C By reacting a compound of the formula wherein-R R and R -havethe'same meaning's as in Formula I, and X and Y, which may be identicaltoor different 'from' each ic'ther; 'are pach' chlorine, -'bromine,alkylthio, alkoxy, amino'br'nitramino, 'wit diamine of the formulaH2N+crr, cHr--NHR wherein R5 has the'ineanings defined imonn'eudti withiqrm l. e th r n-c,. :;-s 1

METHODD' ofthe:Fdrmula IQwherein at bromine.

least one o'f" R ,;R and B is hydrogemiwith chlorine or. Y t 7 t H:

sive, and x-z is an integer from t) to 2, inclusive, or acyl of METHOD EI By hydrolizing a 2-phenylamino-imidazoline-(2) of the formula RQIYwherein R R and R have the same meanings as in Formula I, and R and Rwhich must be different from each other, are each hydrogen or n 2n+1-x(O)x-y( )y where x, y and n have the meanings defined in connection withFormula IX and R is alkyl.

' METHOD G By hydrating a 2-phenylamino-imidazoline-(2) of the formula xwherein R R and R have the same meanings as in Formula I, and R and Rwhich must be different from each other, are each hydrogen or alkenyl of1 to 6 carbon atoms. r 7

METHOD H 7 By reducing a Z-phenylamino-imidazoline-(2) of the formula FI wherein R R and R have the same meanings "as in Formula I, and R1 andR whichmust be different from each other,-are each hydrogen, OXOfilkYlOfthefo'rmula f n n aagtomaz z where R, n and x have the meanings definedin connection with Formula IX, 2 is an integer from 1 to 3, inclutheformula nnzn+l-xt mm cojw ya where R, n, 'x and 'y' have-themeanings'sdefined in connection with Formula'IX and W is chlorine,"hydroxyl, allroxy, or acyloxy, with catalytically, activated hydrogenora'metal'hydride. V

METHOD I I By reacting a 2-phenylamino-imidazoline-(2) of the formula NQ 1 R: I I \N R: I

R16 (XIII) wherein R R and R have the same meaning as in Formula I, andR and R are each alkyl radicals comprising carbonyl, ester, carboxyl,acid chloride or carboxyanhydride functions, with a Grignard reagent.

Depending upon the particular method of preparation which is employed,the reaction product of the Formula I has a hydroxyalkyl or methoxyalkylsubstitutent attached either to the bridge nitrogen atom between thephenyl moiety and the imidazoline moiety or to the nitrogen atom in theimidazoline ring. The location of the substitution can be ascertained bymeans of NMR-spectroscopy. If the substitution is at the bridge nitrogenatom, the four methylene protons of the imidazoline ring show up assingulett at about 6.5 ppm. (r-scale); whereas, if the substitution isat the nitrogen atom of the imidazoline ring, the NMR-spectrum shows acomplex multiplett at about 6-7 p.p.m., instead of the singulett.

Thus, pursuant to method A, the reaction of a2-phenylamino-imidazoline-(2) of the Formula II an oxyalkyl halide ofthe Formula III always yields a compound of the Formula I wherein R ishydrogen and the bridge nitrogen is substituted; on the other hand, thereaction of a compound of the formula II with an aldehyde of the FormulaIV always yields a compound of the Formula I wherein R is hydrogen andthe nitrogen atom in the imidazoline ring is substituted; finally, thereaction of a compound of the Formula II with an epoxide of the FormulaV yields a compound of the Formula I which is substituted at the bridgenitrogen atom or at the ring nitrogen. atom, depending upon the type ofepoxide reactant and the reaction conditions.

The location of the oxyalkyl substitution in the reaction products ofthe Formula I obtained by methods B through I is necessarily predictedby the synthesis process in each case.

The compounds embraced by Formula I are organic bases and therefore formacid addition salts with inorganic or organic acids. Examples ofnon-toxic, pharmacologically acceptable acid addition salts are thoseformed with hydrochloric acid, hydrobromic acid, hydroiodic acid,hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, aceticacid, propionic acid, butyric acid, caproic acid, valeric acid, oxalicacid, malonic acid, succinic acid, maleic acid, fumaric acid, lacticacid, tartaric acid, citric acid, malic acid, benzoic acid,p-hydroxybenzoic acid, paminobenzoic acid, phthalic acid, cinnamic acid,salicylic acid, ascorbic acid, methanesulfonic acid,8-chlorotheophylline or the like.

The following examples further illustrate the present invention and willenable others skilled in the art to understand it more completely. Itshould be understood, however, that the invention is not limited solelyto the particular examples given below.

EXAMPLE 1 2-[N-(2',3' dihydroxy-n-propyl) N (2",6"-dichlorophenyl)amino] imidazoline (2) and its nitrate by method A A mixture consistingof 4.6 gm. (0.02 mol) of 2- [(2,-6' dichloro phenyl) amino] imidazoline(2), 7.5 cc. of 3-chloro-1,2-propanediol and 30 ml. of glycol monomethylester. was heated for 9 hours on a boiling water bath. Thereafter, thereaction mixture was evaporated to dryness in vacuo, the viscous residuewas dissolved in dilute (about 1 N) hydrochloric acid, and the solutionwas fractionally extracted with ether and chloroform at progressivelyhigher pH values. The extracts from the extractions at pH 7, whichcontained the free base, 2 [N (2',3' dihydroxy n propyl) N (2",6"-dichlorophenyl)-amino]-imidazoline-(2), were combined, dried overmagnesium sulfate, treated with activated charcoal and acidified withconcentrated nitric acid until acid reaction to Congo red, whereby 3.0gm. of the nitrate of the base (40.8% of theory) precipitated out inwhite crystalline form. After recrystallization from methanol/ ether,the nitrate of the formula had a melting point of 10l-102 C. The productwas readily soluble in water and ethanol.

EXAMPLE 2 Using a procedure analogous to that described in Example 1,35.3% of theory of 2-[N-(2,3'-dihydroxy-npropyl) N (2" chloro 4"methyl-phenyD-aminrflimidazoline-(2) of the formula and its nitrate wereobtained from 2-[(2'-chloro-4'- methyl-phenyl)-amino] -imidazoline-(2)and 3-chloro-1,2- propanediol.

EXAMPLE 3 1- (fi-hydroxy-ethyl) -2-[ (2,6'-dichloro-phenyl) -amino]-imidazoline-(2) and its hydrochloride by method C A mixture consistingof 18.2 gm. (0.05 mol) of N- (2,6-dichloro-phenyl) Smethyl-isothiouronium hydroiodide, 7.8 gm. (150% of the stoichiometricamount) of N-(fi-hydroxyethyl)-ethylenediamine and ml. of isoamylalcohol was heated to reflux temperature and held there for 12 hours.Thereafter, the clear reaction solution was evaporated to dryness invacuo, and the viscous residue was dissolved in 0.5 N hydrochloric acid.The acid aqueous solution was fractionally extracted with ether atprogressively larger pH values to separate the formed imidazoline basefrom unreacted starting material; the ether extracts obtained at pH 6.5contained 2.0 gm. of base l-(fl-hydroxy-ethyl) 2[(2,6'-dichloro-phenyl)- aminoJ-imidazoline-(Z). The ethereal solutionof the base was dried over anhydrous calcium sulfate, purified bytreatment with activated charcoal, and acidified with etherealhydrochloric acid until acid reaction to Congo red. The precipitateformed thereby was collected by vacuum filtration and dried, yieldingthe hydrochloride, M.P. 234-235 C., of the formula HCl resulting clearreaction solution was evaporated to dryness in vacuo, and the viscousresidue was taken up in dilute hydrochloric acid. The acidic solutionwas vacuumfiltered through charcoal, and the colorless filtrate wasfractionally extracted with ether at progressively higher pH values. Theextracts containing the formed imidazoline base (pH 6.5; proof bythin-layer chromatography) were combined, dried over anhydrous calciumsulfate, and acidified with ethereal hydrochloric aciduntil weakly acidreaction, whereby 4.8 gm. (30.8% of theory) of 1 (B hydroxy-ethyl) 2[(2',4' dichloro-phenyl)- amino] imidazoline (2)hydrochloride, M.P.163-165 C., of the formula Using a procedure analogous to that describedin Example 4, l-(fl-hydroxy-ethyl) 2 [(3'trifiuoromethylphenyl)-amino]-imidazoline-(2), an oily substance, of

the formula was prepared from 'N (3 trifluoromethyl-phenyl)-S-methylisothiouronium hydroiodide and N-(flhydroxyethyl)-ethylene-diamine. The yield was 67.1% of theory.

EXAMPLE 6 Using a procedure analogous to that described in Example 4,l-(fl hydroxy-ethyl) 2 [(4' methoxyphenyl)-amino]-imidazoline-(2), M.P.121-123" C., of the formula GHQ-CH2 O H) was prepared fromN-(4-methoxy-phenyl)-S-methyl-isothiouronium hydroiodide andN-(fi-hydroxy-ethyD-ethylene-diamine. The yield was 40.4% of theory.

EXAMPLE 7 Using a procedure analogous to that described in Ex ample 4, 1([3 hydroxy-ethyl)-2[(5' chloro 2'-methyl-phenyl)-amino]-imidazoline-(2) of the formula n o1 I V cm-crmom 8EXAMPLE 8 Using a procedure analogous to that described in Example 4, 1(B hydroxy-ethyl) 2 [(2',4' dibromophenyl)-amino]-irnidazoline-(2) ofthe formula CHg-CHKOH) was prepared from N-(2,4 dibromo-phenyl)-Smethylisothiouroniurn hydroiodide and N-(ehydroxy-ethyl}ethylene-diamine. Its picrate had a melting point of 177- 1 EXAMPLE 9Using a procedure analogous to that described in Example 4, 1-S-hydroxy-ethyl -2- (2-chloro-4'-methylphenyl)-amino]-imidazoline-(2) ofthe formula was prepared from N-(2-chloro 4 methyl-phenyl)-S-methyl-isothiouronium hydroiodide and N(ii-hydroxyethyl)-ethylenediamine. Its hydrochloride had a melting pointof ISO-182 C.

EXAMPLE 10 1 (,9 hydroxy ethyl) 2 [(2' chloro 4-methylphenyl)-amino]imidazoline-(2) and its hydrochloride by method C Amixture consisting of 5.2 gm. (0.0511191) of N-(B-hydroxy-ethyl)-ethylenediamine and 50 ml. of absolute chloroform wasadded dropwise at 5 C. over a period of 40 minutes to a solution of 11.1gm. (0.05 mol) of 2- chloro 4 methylphenylisocyanide dichloride in,50ml. of absolute chloroform, and the resulting mixture'was allowed tostand at room temperature overnight. T here'- after, the chloroform wasevaporated in vacuo under gentle conditions, the residue was dissolvedin 2 N hydrochloric acid, the resulting solution was purified byfiltration through activated charcoal, and the filtrate was fractionallyextracted with ether at progressively larger pH values. The etherextracts obtained at pH 7, which contained the imidazoline base,.werecombined, dried over magnesium sulfate, and acidified with etherealhydrochloric acid until weakly acid reaction to .Congo red. The

' resulting acidic solution was cooled for some time on an ice bath,whereby the hydrochloride of l-(fl-hydroxyethyl)-2-[(2'-chloro 4'methyl-phenyl)-amino]-imidazoline-(2), M.P. 182 C., crystallized out asa white crystalline substance.

EXAMPLE 11 Using a procedure analogous to that described in Example 10,l-(fl hydroxy ethyl) 2 [(4' cyanophenyl) aminoJimidazoline (2), M.P. 126C., of the formula was prepared from 4-cyano-phenylisocyanide dichlorideand N (,3 hydroxy-ethyl) ethylenediamine. Its hydrochloride (yield: 9.7%of theory) had a melting point of 208-210 C. i 2 z:

tiA'mix'ture consisting of (0.01 mol) of N (2 chloro- 4" -'"methyl-":;phenyl) -N"-,nitro-guanidine (prepared by reacting 1.5 gm. ofZ-chloro-p-toluidine with 1.5 gm. of N-methyl-N-nitroso N'-.- nitroguanidine pursuant to Adee1 ',JJ,,Chem.1Soc.;'1965, 474), 1.1 gm. (0.01mol) of N -(fi-lgi 'yjdroxy-ethyl)-ethylenediamine and 20 ml. ofabsolute ethanol was refluxed for 8 hours, while stirring. Thereafter,'.the .ethanqlfwas evaporated in vacuo, the

residuef'ivas 'taken up 'in dilute (about 2 N) hydrochloric'acid, theinsoluble matter was filtered off, and

thefiltrate wa'sfractionally extracted with chloroform at progressivelylarger pH value. The extracts obtained at pH 7, whichcontained theimidazoline base, were combined, driedover. anhydrous calcium sulfate,and the chloroform was evaporated in" vacuo. The oily residue,l-(d-liydroxy-ethyl) -2-[(2-chloro 4' methyl-phenyl)- amino]imidaz oline-(2), was dissolved in a small amount of absolute ether, and theresulting. solution was acidified withfethereal hydrochloric acid untilacid reaction to Congo red. The crystalline precipitate formed therebywas collected by vacuurnfiltration,washed and dried, yielding 0.1 gm. ofl-(B-hydroxy-ethyl)-2-[(2'-chloro-4'- methyl-phenyl) ,.--amino]imidazoline (2), M.P. 179- 18;l-.? ..C.- 5 f 5 g EXAMPLE 13 2 [Nme'thoxy-methyl)-N-.( 2',6"-dichloro-phenyl)- hrhind] imidazoline-(2) bymethod A 2.3 gm. (0.01 manor 2 [(2,6' 4 dichloro-phenyl)-amino]-imidazoline-(2) and 1.2 gm. (0.015 mol) of chloro-dimethyletherwere dissolved in 10 ml. of methanol, and the solution was refluxed forthree hours. Thereafter, the methanol and the excess, unreactedchlorodimethylether were distilled off, and the residue was taken up ina small amount of water. The resulting aqueous solution was fractionallyextracted with ether at progressive higher pH values, and uponevaporation of the extract-obtained at pI-lW11 -12, 0.6 gm. (22% oftheory) of 2-[N-(m etht ury-methyl) N(2',6-dichlorophenyl)-amino]-imidazoline-(2), M.P. 120123 C., of

the formula I. w l

crystallized out.

1 .EX-AMPLE 14;

' aipro'cedure analogous to that described in Exampie 13,'Z-IN-(ethQxY-methyD N-(2,6' dichlorophenyl)-amino]-imidazoline-(2),MLP. 159-161" C., was preparedfrom 2[(2,6 dichloro phenyl) amino]- imidaaoline-"(D and chloroinethyl ethylether.

g1; M E' -1= (hydroxy.-

ethyl )-2- (2' ,6'-dichloro-phenyl) -'amino] imidaz'oline(2-)by'method'A- a f; Amixtulre consistiiijgjo fA16 gmi(}02 mol) "at z ttif.chloro phen amino]: "imidaz'oline '(2) 1.5 gmT'of faq bus '40%- of 0formaldehyde (0.02 'mol') and '25 ml.

"ofnithandl wasiheatd in"asealed tube (ma-boiling w'ate'r b'at'lifoi--'10- hours'.Thereafter;' the-"reactiori mixture was evaporated todryness in vacuo, the oily residue was t'akerr'zup in dilutelhydro'chlo'ricacid, and the acid-aqueous solutionwasifractionally'rextracted'iwith ether. lat progressi ely zlarger'pI-Izvalues; the-stepwise in crease.=.of..the pH was effected byaddition of 2 N sodium hydroxide. The

N in H I CHaOH was obtained.

EXAMPLE 16 l-(fi-hydroxy-ethyl)-2-[ (2',6'-dichloro-phenyl)-amino]-imidazoline-(2) and its hydrochloride by method E A mixture consistingof 3 gm. of l-(fi-acetoxy-ethyD- 2-[(2',6-dichloro phenyl) amino]imidazoline (2) hydrochloride (M.P. 200-203" C.) and 25 ml. of 2 Nhydrochloric acid was refluxed for about 2 hours. Thereafter, thereaction mixture was evaporated in vacuo, and the residue was admixedwith ether, whereby the hydrochloride of l-(fl-hydroxy ethyl) 2 [(2',6'dichlorophenyl)-amino] -imidazoline-(2), M.P. 225-227 C., crystallizedout. For purification, the hydrochloride was dissolved in water, and theaqueous solution was made alkaline with 2 N sodium hydroxide, wherebythe free base was liberated, which was extracted with chloroform. Thechloroform extract was acidified with ethereal hydrochloric acid, andthe precipitate formed thereby was collected and recrystallized frombutanol/ether. 0.9 gm. of l-(B hydroxy ethyl) 2 [(2,6 dichloro phenyl)-amino]-imidazoline-(2) hydrochloride, M.P. 234235 C., was obtained.

EXAMPLE 17 1- b-hydroxy-ethyl) -2-[ (2',6'-dichloro-phenyl) -amino]imidazoline-(Z) and its hydrochloride by method H A solution of 0.8 gm.of l-(fl-acetoxy-ethyl)-2-[(2',6'- dichloro-phenyl)-amino]-imidazoline(2) in 40 ml. of absolute ether was slowly added dropwise to a mixtureof 0.2 gm. of lithium aluminum hydride and 40 ml. of absolute ether,whereby the temperature of the mixture rose slightly. Thereafter, thereaction mixture was refluxed for three hours, then poured into icewater, and the aqueous mixture was fractionally extracted with ether atprogressively larger pH values. The extracts containing the desiredreaction product were combined, dried over magne sium sulfate, and thenacidified with ethereal hydrochloric acid until acid reaction to Congored. The precipitate formed thereby was collected by vacuum filtrationand washed with absolute ether, yielding 0.6 gm. (81.6 of theory) ofl-(B-hydroxy ethyl) 2 [(2,6 dichlorophenyl) amino] imidazoline-(Z)hydrochloride, M.P., 234-235 C.

EXAMPLE 18 A solution of 3.2 gm. of l-[2'-(carbo-n-butoxy)-n propy l-(1')]-2-[(2"-tolyl)-amino] i'midazoline (2) in 40 ml. of absolute etherwas slowly'added 'dropwise toa mixture'of 0.5 gm. of lithium aluminumhydride and 50 ml. of absolute ether at room temperature, whilestirring, whereby the temperature of the mixture rose slightly. Thereaction mixture was then refluxed for three hours, allowed to cool andadmixed with an aqueous 20% solution of potassium sodium tartrate. Theresulting mixture was made alkaline with sodium hydroxide, theimidazoline base liberated thereby was extracted with several portionsof chloroform, and the extracts were combined, dried over magnesiumsulfate, and the chloroform was evaporated in vacuo, leaving as theresidue 2.3 gm. of thin-layer chr-' matographically andelemental-analytically pure 1-[3'- hydroxy-2'-methyl n propyl (1)] 2[(2" tolyl)- amino]-imidazoline-(2), a viscous oily substance, of theformula Analysis.-Calculated (percent): C, 67.99; H, 8.56; N,

16.99; 0, 6.47. Found (percent): C, 67.90; H, 8.54; N, 16.07; 0, 7.19.

EXAMPLE 19 2- [N-(2'-hydroxy-n-propyl-1')-N-(2","-dichlorophenyl)-amino]-imidazoline-(2). by method G A mixtureconsisting of 2.5 gm. of 2-[N-allyl-N-(2,6'-dichloro-phenyl)-amino]-imidazoline-(2) (M.P. 130- 131 C.) and 50 ml.of aqueous 50% sulfuric acid was stirred for 10 hours at roomtemperature, then heated for 3-4 hours at 100 C.; and allowed to cool toroom temperature. The resulting dark reaction mixture was adjusted to apH of 10 with aqueous 50% potassium hydroxide while adding ice,extracted several times with chloroform, the extracts were combined anddried over magnesium sulfate, and the chloroform was evaporatedtherefrom. The residue was triturated with ether, whereby itcrystallized throughout, and the crystals were collected by vacuumfiltration and washed with ether, yielding 0.3 gm. (11.2% of theory) of2-[N-(2'-hydroxy-n-propyl- 1)-N-(2,6"-dichloro-pheny1)-amino]imidazoline-(Z), M.P. 169-171 C., of the formula l l I m-omom-cn.

EXAMPLE 20 2-[N-(2',6-dichloro-pheny1)-N- p-hydroxy-ethyD-amino]-imidazoline-(2) by method A A mixture consisting of 6.9 gm. (0.03mol) of 2-(2,6'- dichloro-phenyl-amino)-imidazoline-(2), 10 ml. ofethylene oxide and 100 ml. of absolute benzene was heated for 8 hours at120 C. Thereafter, the reaction mixture was evaporated in vacuo, theresidue was taken up in dilute hydrochloric acid, the resulting acidsolution was fractionally extracted with ether at progressivelyincreasing pH values to remove impurities, and the desired reac- ,tionproduct was extracted with chloroform. The combined chloroform extractswere chromatographed on about 120 gm. of aluminum oxide (neutral,activity stage III), the pure eluate fractions were combined andevaporated in vacuo, and the oily residue was caused to crystallize bytr'ituration with ether, yielding 2.5 gm. (30.1% .of

theory) of pure, white 2-[N-(2T,6'-dichloro phenyl)-N- .(fi-hydroxyethyl)-amino]-imidazoline (2), M.P. 145- 149 c., ofthe formula p EXAMPLE"21 1-[3-hydroxy-2,3'-dimethyl n butyl,-( 1')]2-(2",6"-dichlorophenyl-amino)-imidazoline-(2) and its hydrochloride bymethodI .1 1 A solution of 5.3 gm. of"1 -[-2-(carbon-butoxy)-npropyl-(1')] 2 [(2",6" dichloro-phenyl) aminoHmid azoline-(Z) in ml. ofabsolute 'etherwasa'dded drop wise to a gently refluxing Grignard're'a'gent' pr eparedfrom' 1.74 gm. of magnesium, '11'.2 gmfof methyliodide" and 100 ml. of absolute ether, and the-reaction mixturewas thenrefluxed for 2 hours more. Thereafter, the" reaction mixture wasdecomposed with-dilute hydrochloric acid and ice, the aqueous mixturewas extracted 'sever'altime's with ether, and the ether extractswerediscarded; The aqueous phase was now made alkaline -withsodium'hydroxide, and the precipitate" formed thereby wascentrifuged OEand also discardedsThe liquid phase wasextracted repeatedly withchloroform, and-the combined extracts were dried over inagnesiumsulfateand evaporated, leaving 2.3 gm. of a viscous, slightly 'yellowoil whichwas identified to be the raw free base l-[If-hy' droxy-2',3'-dimethyl nbutyl-(1' )]2-(2", "-dichloro phenyl-amino)-imidazoline-(2). I j Thebase was converted withether'eal hydrochloric-acid into its rawhydrochloride (M.P. 194-198 C.), which was purified by chromatography onaluminum oxide (neutral, activity stage III) with chloroform as the:solvent. The thin-layer chromatographically uniform hydrochloride, M.P.201-204 C., of the formula was obtained. EXAMPLE 22 2 [N (2,6' dichlorophenyl) N s hydroxyethyl)-amino]-imidazo1ine- (2) and its hydrobromideby method F amino]-imidazoline-' '(2 M.P.. -147 -c.;wj1'ii.cii pinyin.tobe thin-layer sample.

chr'omatographicallyidentical toa known The compounds toi the presen..mven1 on, that is, those embraced by Formula I and "their non-toxicacid addition salts, I have useful pharmacodynamic properties. Moreparticularly, the compounds ofthe instant invention exhibit-hypotensiveactivities in warm-blooded animals, such as rabbits, dogs and cats.

i For pharmaceutical purposes thec'ompounds according to the presentinvention are administered to warm-blooded animals perorally, enterallyor parenterally as active ingredient's in customary dosage unitcompositions, that is, compositions in-dosage unitform consistingessentially of an inert pharmaceutical-carrier and one effective dosageunit of the active ingredient, such as tablets, coated pills, capsules,wafers, powders,"solutions, suspensions, emulsions, syrups,suppositories and the like. One effective dosage unit of the compoundsaccording to the present invention is fro'm'"0.0083 to 1.67- mgm./kg.body weight, preferably 0.05 to 0.5 mgm./kg. body weight.

Such dosage unit compositions may also contain an effective dosage unitvof another hypotensive compound, such as a benzothiadiazine and/or ofactive ingredients with another pharmacodynamic activity, such asspasmolytics, salureticsg dimetics,- analgesics, hyperotics or the'like..53 l The following examples illustrate a few dosage unit compositionscomprising a compound of the present invention as an active ingredientand represent the best modesc'ontemplatedof putting the invention intopractical use. The parts are parts by weight unless otherwise specified.EXAMPLE 23 Coated pills The pill core composition was compounded fromthe following ingredients:

Parts 1 (,3 hydroxy-ethyl)-2-[(2',6'-dichloro-phenyl)-amino]-imidazoline-(2)-hydrochloride Lactose Corn starch Secondarycalcium phosphate "a Soluble starch Colloidal silicic acid Magnesiumstearate Total 250.0

Preparation: The imidazoline compound was intimately admixed with thelactose, the corn starch, the calcium phosphate and the colloidalsilicic acid, the resulting mixture was moistened with an aqueoussolution of the soluble starch, the moist mass was granulated by forcingit through a fine-mesh screen, and the granulate was dried and admixedwith the magnesium stearate. The resulting composition was compressedinto 250 mgm.-pill cores, which were then coated with a thin shellconsisting essentially of a mixture of sugar, talcum and gum arabic, andfinally polished with beeswax. Each coated pill contained 15 mgm. of theimidazoline compound and was an oral dosage unit composition witheffective hypotensive action.

EXAMPLE 24 Hypodermic solution The solution was compounded from thefollowing ingredients:

Parts Z-[N-methoxymethyl N (2,6' dichlorophenyD- amino]-imidazoline-(2)hydroiodide Sodium chloride Distilled water, q.s. ad 2000.0 parts byvol.

Preparation: The imidazoline compound and the sodium chloride weredissolved in a suflicient amount of distilled water, the solution wasdiluted with additional distilled water to the indicated volume, thedilute solution was filtered until free from suspended particles, andthe filtrate was filled into 2 cc.-ampules in an atmosphere of nitrogenand under aseptic conditions. The filled ampules were then sealed andsterilized for 20 minutes at C. Each ampule contained 2 mgm. of theimidazoline compound and its contents were an intravenously injectabledosage unit composition with effective hypotensive action.

Analogous results were obtained when any one of the other imidazolinesembraced by Formula I or a non-toxic acid addition salt thereof wassubstituted for the particular imidazoline in Examples 23 and 24.Likewise, the amount of active ingredient in these illustrative examplesmay be varied to achieve the dosage unit range set forth above, and theamounts and nature of the inert pharmaceutical carrier ingredients maybe varied to meet particular requirements.

While the present invention has been illustrated with the aid of certainspecific embodiments thereof, it will be readily apparent to thoseskilled in the art that the invention is not limited to these particularembodiments, and that various changes and modifications may be madewithout departing from the spirit of the invention or the scope of theappended claims.

We claim:

1. A compound of the formula wherein R R and R are each hydrogen,chlorine, fluorine, bromine, alkyl of 1 to 3 carbon atoms or alkoxy of 1to 3 carbon atoms, or one of them is cyano or trifluoromethyl and theothers are hydrogen, and R and R which must be different from eachother,

are each hydrogen or .Qit

wherein R is chlorine, bromine, trifiuoromethyl or c'yano,

R is hydrogen, methyl, chlorine or bromine,

R is monohydrox'y-al'kyl of l to 4 carbon atoms, 2,3-

dihydroxy-propyl or methoxymethyl, and

R is monohydroxy-alkyl of 1 to 6 carbon atoms, or a non-toxic,pharmacologically acceptable acid addition salt thereof.

15 3. A compound of the formula N. @a-f N 4 RI I a H N 1 I wherein R ismonohydrox'y-alkyl of 1 to 4 carbon atoms, 2,3-

dihydroxy-propyl or methoxymethyl, and R is monohydrox'y-alkyl of 1 to 6carbon atoms, or a non-toxic, pharmacologically acceptable acid additionsalt thereof.

4. A compound according to claim 3, which is l-(fi hydroxy-ethyl) 2[(2',6' dichloro phenyl)-amino]- imidazoline-(2) or a non-toxic,pharmacologically acceptable acid addition salt thereof.

5. A compound according to claim 3, which is 2-[N- methyloxymethyl N(2,6' dichloro-phenyl)-amino]- imidazoline-(2) or a non-toxic,pharmacologically acceptable acid additicn salt thereof.

6. A compound according to claim 3, which is 2-[=N- (2',3' dihydroxy npropyl-l') N (2",6" dichlorophenyD-amino] -imidazoline-('2) or anon-toxic, pharmacologically acceptable acid addition salt thereof..

7. A compound according to claim 3, ,which is l-hydroxymethyl 2 [(2,6 4dichloro phenyl {amino1-imidazoline-(Z) or a non-toxic,pharmacologically acceptable 5 acid addition salt thereof.

8. A compound accordingto claim 3,'which is 2-[N (2-hydroxy-n-propyl-1)-'N (2",6" dichloro-phenyl)- amino]-imidazoline-(2) or a non-toxic,pharmacolog'ically 10 acceptable acid adidtion saltfthereof. l a

References Cited FOREIGN PATENTS 7 1,448,765 7/ 1966- France 260309.61,506,407 11/1967 France ..d 2605-3096 1,506,408 11/1967 France l260-309.-6 796,997 6/1958 GreatBritain ..-260 309.6 1,016,514- 1/1966 GreatBritain- 260-30945 1,034,938 7/ 1966 Great Britain 260-'-309.6

OTHER REFERENCES I v I McKay et al.: Chem. Abst., vol. 52, col. 7288(1958) Reisner et al.: Chem. Abst., v01. 72, .No. 55335e Tronche et al.:Chem. Abst., vol. 55, col. l1396 (1961).

Tuzun: Chem. Abst.', vol. 70, N0. 573,325j (1969).

NATALIE TROUSOF, Primarfnxdmindr' Cl X.R.

